Inhibition of the bromodomain and extra-terminal family of epigenetic regulators as a promising therapeutic approach for gastric cancer

Abstract

Purpose Epigenetic dysregulation is a common characteristic of cancers, including gastric cancer (GC), and contributes to cancer development and progression. Although the efficacy of BET (an epigenetic regulator) inhibition has been demonstrated in various cancer types, predictive genetic markers of its efficacy in GC are currently lacking. Therefore, we aimed to identify markers that predict the response of BET inhibition in GC and, suggest an effective treatment regimen through combined therapy. Methods The effect of BET inhibition was evaluated using iBET-151, a small-molecule inhibitor of BET proteins, in a large panel (n = 49) of GC cell lines and xenograft mouse models. Comprehensive genetic information was used to identify cell lines sensitive to iBET-151. Flow cytometry, Western blotting, and colony-formation and migration assays were used to evaluate the effects of iBET-151 and/or paclitaxel. The synergistic effect of iBET-151 and paclitaxel was evaluated using an organoid model. ResultsWe found that iBET-151 showed a modest growth-inhibitory effect in GC cells (73%, 36/49). iBET-151 inhibited tumorigenicity in vitro and significantly promoted cell cycle arrest and apoptosis. Based on comprehensive genetic information analysis in relation to BET family expression, we found that BRD4 was highly expressed in the iBET-151-sensitive cell lines. We also identified WNT5B and IRS2 as potential biomarkers that are predictive for sensitivity to iBET-151. In GC xenograft model mice, iBET-151 significantly decreased tumor volumes and Ki-67 and BRD4 expression. Combination treatment showed that iBET-151 increased the sensitivity of GC cells to paclitaxel in approximately 70% of the cell lines (34/49) tested. iBET-151 plus paclitaxel significantly promoted cell cycle arrest and apoptosis and suppressed c-Myc, Bcl-2 and Bcl-xL expression. In GC organoids, iBET-151 and paclitaxel showed a synergistic effect. Conclusions Collectively, our data suggest that iBET-151 is a potential therapeutic agent for GC, especially in combination with paclitaxel, and that WNT5B and IRS2 may predict iBET-151 sensitivity.

Wnt signaling in gastric cancer: current progress and future prospects

“…In 2019, Xu et al (28) reported that inhibition of zinc-finger transcription factor 1 (ZEB1) reduced the level of WNT5A in GC, induced apoptosis and inhibited the proliferation and migration of GC cells. Current research on WNT5B is not very clear, although it can predict the sensitivity of the epigenetic regulator BET inhibitor iBET-151 to inhibit the growth of gastric cancer, especially when combined with paclitaxel (29). Therefore, it may be possible to predict the effect of chemotherapy in gastric cancer by WNT5B.…”

“…b-Catenin responsive transcription inhibitor 3/5 (iCRT3/5), which mainly blocks b-catenin-TCF4 interactions, is in the preclinical stage of gastric cancer treatment, and it can kill gastric cancer malignant cells and inhibit gastric cancer development (88). LF3 is a 4-thioureidobenzenesulfonamide derivative that profoundly inhibits the interaction between b-catenin and TCF4 and reduces the expression of GPX4, inducing iron-induced death in gastric cancer cells (29). In 2018, Wang et al Found that XAV939, a small-molecule inhibitor (SMI), increases degradation of b-catenin by stabilizing Axin and inhibits gastric cancer invasion and metastasis (92).…”

“…Aberrant activation of glutathione peroxidase 4 (GPX4), a key antioxidant enzyme, confers resistance to radiation and chemotherapy-induced iron death to cancer cells ( 72 ). The β-catenin/TCF4 transcriptional complex in the Wnt pathway directly binds to and induces the expression of GPX4, which attenuates the production of cytosolic lipid ROS, leading to iron death resistance ( 29 ). H. pylori infection upregulates GPX4 expression and activity through TCF4, leading to a high antioxidant state of cancer cells and inhibition of iron-induced death; thus, GPX4 may be a potential target to enhance chemosensitivity in patients with advanced GC ( 29 ).…”

Roles of Bromodomain Extra Terminal Proteins in Metabolic Signaling and Diseases

“…Atherosclerosis [44] Diabetes [45] Fabry disease [12] Chronic kidney disease [46] IBET-762 (GSK-525762) BD1 and BD2 from BRD2,3,4,T Neoplasm [12] Testis carcinoma [47] Midline carcinoma [12] IBET-151 BD1 and BD2 from BRD2,3,4,T MLL-fusion leukemia [48] Colorectal ctumorsancer [42] Gastric cancer [49] Vismodegib-resistant esophageal adenocarcinoma [50] Rheumatoid arthritis [15] Melanoma [51] Myeloma [52] MK8628/OTXO15 BRD2,3,4…”

Inhibition of BRD4 enhanced the tumor suppression effect of dasatinib in gastric cancer

“…Inhibition of BRD4 has been reported to suppress GC progression and metastasis by destabilizing snail family transcriptional repressor 1 (SNAIL) or downregulating c-myc expression [ 5 , 6 ]. BET bromodomain inhibitors, such as iBET-151, ARV-825, and JQ1, are employed in GC in vivo and in vitro and demonstrate effective antitumor activity [ 10 – 12 ]. Therefore, BRD4 is a promising therapeutic target for GC treatment.…”